Cis-regulatory hubs: a new 3D model of complex disease genetics with an application to schizophrenia.
Chromatin
/ genetics
Computational Biology
/ methods
Enhancer Elements, Genetic
/ genetics
Epigenesis, Genetic
/ genetics
Gene Expression
/ genetics
Gene Expression Regulation
/ genetics
Humans
Models, Genetic
Multifactorial Inheritance
/ genetics
Polymorphism, Single Nucleotide
/ genetics
Promoter Regions, Genetic
/ genetics
Schizophrenia
/ genetics
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
12
07
2021
revised:
12
01
2022
accepted:
14
01
2022
entrez:
28
1
2022
pubmed:
29
1
2022
medline:
29
3
2022
Statut:
epublish
Résumé
The 3D conformation of the chromatin creates complex networks of noncoding regulatory regions (distal elements) and promoters impacting gene regulation. Despite the importance of the role of noncoding regions in complex diseases, little is known about their interplay within regulatory hubs and implication in multigenic diseases such as schizophrenia. Here we show that cis-regulatory hubs (CRHs) in neurons highlight functional interactions between distal elements and promoters, providing a model to explain epigenetic mechanisms involved in complex diseases. CRHs represent a new 3D model, where distal elements interact to create a complex network of active genes. In a disease context, CRHs highlighted strong enrichments in schizophrenia-associated genes, schizophrenia-associated SNPs, and schizophrenia heritability compared with equivalent structures. Finally, CRHs exhibit larger proportions of genes differentially expressed in schizophrenia compared with promoter-distal element pairs or TADs. CRHs thus capture causal regulatory processes improving the understanding of complex disease etiology such as schizophrenia. These multiple lines of genetic and statistical evidence support CRHs as 3D models to study dysregulation of gene expression in complex diseases more generally.
Identifiants
pubmed: 35086934
pii: 5/5/e202101156
doi: 10.26508/lsa.202101156
pmc: PMC8807870
pii:
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2022 Mangnier et al.
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